In spite of progress against prostate cancer (PC), treatment of the disease still exacts significant financial and quality-of-life costs. And, as treatment is not always effective, PC still kills some 30,000 American men each year. Prevention, including chemoprevention, remains a potentially attractive approach. Among the numerous chemopreventive agents, selenium appears promising; its chemopreventive utility was strongly suggested by the Nutritional Prevention of Cancer (NPC) trial, led for several years by the PI. In the NPC trial, men assigned to supplementation by 200 meg selenium/day experienced 50% lower PC mortality than men assigned to placebo; these results helped to lead to the trials of selenium for men with high grade prostatic intraepithelial neoplasia (HGPIN) and to the Selenium and Vitamin E Chemoprevention Trial (SELECT). The mechanisms underlying the chemopreventive action of selenium in PC are poorly understood. Results from our laboratory indicate that selenium alters androgen signaling, with decreased expression of the androgen receptor (AR), and AR target genes such as prostate-specific antigen (PSA), kallikrein 2 (KLK2), 24-dehydrocholesterol reductase (DHCR24), cell division cycle 6 (CDC6), and hepatocyte nuclear factor 3a (HNF3a). These findings need to be tested in human populations; we propose to do this by randomizing prostate cancer patients scheduled for brachythrapy and prostatectomy to pretreatment supplementation by daily dose of 400 meg selenomethionine, or to placebo. After 8-9 weeks of supplementation, at treatment, biopsy core samples will be obtained from the peripheral zone of the prostate and frozen, then microdissected, with benign tissue analyzed by qRT-PCR for expression of AR as the primary endpoint, and for PSA, KLK2, DHCR24, CDC6 and HNFSa as secondary endpoints. In addition, we will explore the hypothesis that the activity of thiol methyltransferase, a key enzyme in selenium metabolism, correlates with the response to selenomethionine supplementation. This study will provide key in vivo, human data on the mechanisms of selenium's action in the prostate, and greatly help interpret the results of the important chemoprevention trials such as HGPIN and SELECT.